This invention relates to pharmacology, and to the use of dextromethorphan as a cough suppressant.
Dextromethorphan (frequently abbreviated as DM) is the common name for (+)-3-methoxy-N-methylmorphinan. It widely used as a cough syrup, and is described in references such as Rodd 1960 (full citations to articles are provided below) and Goodman and Gilman's Pharmacological Basis of Therapeutics. Briefly, DM is a non-addictive opioid comprising a dextrorotatory enantiomer (mirror image) of the morphinan ring structure which forms the molecular core of most opiates.
The cough-suppressing activity of DM is believed to be due primarily to its activity at a class of neuronal receptors known as sigma receptors. These are often referred to as sigma opiate receptors, but there is some question as to whether they are opiate receptors, so many researchers refer to them simply as sigma receptors, or as high-affinity dextromethorphan receptors. They are inhibitory receptors, which means that their activation by DM or other sigma agonists causes the suppression of certain types of nerve signals, apparently including the signals that mediate coughing.
Dextromethorphan also acts at another class of receptors known as N-methyl-D-aspartate (NMDA) receptors, which are one type of excitatory amino acid (EAA) receptor. Unlike its agonist activity at sigma receptors, DM acts as an antagonist at NMDA receptors, which means that DM suppresses the transmission of nerve impulses mediated via NMDA receptors. Since NMDA receptors are excitatory receptors, the activity of DM as an NMDA antagonist also leads to the suppression of certain types of nerve signals, which may also be involved in some types of coughing.
Due to its activity as an NMDA antagonist, DM and one of its metabolites, dextrorphan, are being actively evaluated as possible treatments for certain types of excitotoxic brain damage caused by ischemia (low blood flow) and hypoxia (inadequate oxygen supply), which are caused by events such as stroke, cardiac arrest, and asphyxia. The anti-excitotoxic activity of dextromethorphan and dextrorphan, and the blockade of NMDA receptors by these drugs, are discussed in items such as Choi 1987, Wong et al 1988, Steinberg et al 1988, and U.S. Pat. No. 4,806,543 (Choi 1989).
Dextromethorphan has also been reported to suppress activity at neuronal calcium channels (Carpenter et al 1988).
Dextromethorphan and the receptors it interacts with are further discussed in Tortella et al 1989, Leander 1989, Koyuncuoglu & Saydam 1990, Ferkany et al 1988, George et al 1988, Prince & Feeser 1988, Feeser et al 1988, Craviso and Musacchio 1983, and Musacchio et al 1988.
Because of its activity as an NMDA antagonist which may be able to block excitotoxic damage to neurons, DM has become of interest as a potential therapy to treat progressive neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS, also called Lou Gehrig's disease), all of which are suspected of containing an excitotoxic aspect of their etiology. Accordingly, the Applicant, a neurologist who specializes in working with ALS patients, undertook a study of DM to determine whether it might be able to retard the progress of ALS.
Regrettably, DM was not able to slow down the progressive loss of strength, slurring of speech, and other muscular symptoms suffered by those patients. However, during the course of that study, other important findings emerged, as discussed below.